It has been generally believed that the brain's energy demands were normally met by the consumption of oxygen and glucose in stoichiometric amounts for the complete oxidation of glucose to oxygen and water. This belief was recently challenged because of PET studies reporting that glucose is used in excess of equivalent oxygen consumption during cognitive challenges or sensory stimulation. This has led to the now popular speculation that functional activity in brain is supported by energy derived from glycolysis and litt,e if at all, from oxidative metabolism. Under conditions of limited oxygen supply, this would be expected, but for this to happen in the presence of adequate O2 violates traditional concepts of energy metabolism. We have, therefore, examined in conscious rats in vivo the metabolism of [14C]glucose in rat brain under conditions in which glucose consumption was increased by functional activation. Cerebral arteriovenous O2 glucose, and lactate differences and total and 14C-labeled levels of lactate, glycogen, and glucose in the brain at the end of the period for each functional state were measured. 14C- labeling of the brain lactate pool was increased 3-fold during K+- stimulated metabolic activity. About 20% of the glucose taken up by brain was lost to the blood as lactate, and similar quantities must have been transported from activated tissue to other brain regions. Thus, trafficking of intermediary metabolites within the brain can be extensive, a new, unexpected finding. During and following sensory stimulation lactate accumulation in the brain and loss to the blood were much smaller even though the oxygen/glucose uptake ratio was reduced, indicating that glucose utilization exceeded the stoichiometric equivalent of the oxygen consumption during the stimulation period . Also, brain levels of glycogen, which is localized mainly in astroglial cells, was diminished during sensory functional activation. During recovery from the sensory stimulation, however, the oxygen/glucose ratio rose to much higher levels that that for complete stoichiometry, indicating greater oxygen consumption than equivalent glucose utilization. These results, therefore, show that it is not true that functional activaty depends only on glycolytic and not oxidative metabolism. The apparent uncoupling between oxygen glucose metabolism is only temporal; the excess glucose utilization leads to accumulation of glucose metabolites in intermediate pools during functional activation which are then oxidized further to CO2 and H2O over an extended period of time during recovery. Manuscripts on this work have been published or are in press. This project is now discontinued here because the professional staff members who were working on it have left the laboratory and are now continuing these studies at their new locations. Publications Dienel, G.A., Cruz, N.F., Adachi, K., Sokoloff, L., and Holden, J.E. (1997) Determination of local brain glucose level with [14C]methylglucose: Effects of glucose supply and demand. Am J. Physiol. (Endocrinol. Metab. 36), 273: E839-E849. Madsen, P.L., Cruz, N.F., Sokoloff, L, and Dienel, G.A. (In press) Cerebral oxygen/glucose ratio is low during sensory stimulation and rises above normal during recovery: Excess glucose consumption during stimulation is not accounted for by lactate efflux from or accumulation in brain tissue. J. Cereb. Blood Flow Metab. (Accepted August 14, 1998).